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1.
Cell Transplant ; 30: 963689721993769, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33840257

RESUMEN

Until July 29th, the number of confirmed coronavirus (COVID-19) cases worldwide has risen to over 16 million, within which 655 k deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) emerges as the 11th global pandemic disease, showing the highest infectivity and lowest infection fatality rate. In this review, we compare the immunopathology among SARS-CoV, Middle East respiratory syndrome coronavirus, and SARS-CoV2. SARS-CoV2 is similar to SARS-CoV; it can cause lymphocytopenia and a rising granulocyte count. Here we point out the human body and concentrated society make for an excellent incubator for virus evolution. Most research energies put into developing the SARS-CoV2 vaccine are trying to block virus infection. Sixty-five percent of severe patients die with multiple organ failure, inflammation, and cytokine storm, which indicates that the patient's immune system maintains functionality. Finding a way to trigger the specific T cell subset and plasmablast in our body is the best shot to get away with SARS-CoV2.


Asunto(s)
/inmunología , /inmunología , Animales , Coronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Virus del SRAS/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/patología
2.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807632

RESUMEN

The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune system. Innate lymphoid cells (ILCs) are found abundantly in the thoracic and peritoneal cavities, and they are crucial in first defense against pathogenic viruses and bacteria. Nanomaterials (NMs) can enter the cavities intentionally for medical purposes, or unintentionally following environmental exposure; subsequent serosal inflammation and cancer (mesothelioma) has gained significant interest. However, reports on adverse effects of NM on ILCs and other components of the serosal immune system are scarce or even lacking. As ILCs are crucial in the first defense against pathogenic viruses and bacteria, it is possible that serosal exposure to NM may lead to a reduced resistance against pathogens. Additionally, affected serosal lymphoid tissues and cells may disturb adipose tissue homeostasis. This review aims to provide insight into key effects of NM on the serosal immune system.


Asunto(s)
Sistema Inmunológico/inmunología , Nanoestructuras/química , Cavidad Peritoneal/fisiología , Membrana Serosa/inmunología , Cavidad Torácica/inmunología , Animales , Homeostasis/inmunología , Humanos , Inflamación/inmunología , Linfocitos/inmunología
3.
Med Sci Monit ; 27: e930853, 2021 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-33844678

RESUMEN

BACKGROUND COVID-19 has become a worldwide epidemic disease and is a public health crisis. We aim to provide evidence for clinical diagnosis and assessment of severity by analyzing patients' clinical data and early laboratory results and exploring the correlation between laboratory results and clinical classification. MATERIAL AND METHODS We enrolled 283 cases of suspected and diagnosed COVID-19 from 16 hospitals in Jiangsu Province from January to April 2020. The routine laboratory blood examinations, T lymphocyte subsets, and biochemical and coagulation function among different populations were contrasted by t test and chi-square (χ²) test. RESULTS Cough, fever, and dyspnea could be helpful to diagnose COVID-19 infection (P<0.05). Patients who were older or had comorbidities tended to become severe and critical cases. Among all the patients, the most obvious abnormal laboratory results were higher neutrophil count, CRP, total bilirubin, BUN, CRE, APTT, PT, and D-dimer, and lower blood platelet and lymphocyte count. CD3⁺ T cell, CD4⁺ T cell, and CD8⁺ T cell counts gradually decreased with exacerbation of the disease (P<0.05). CONCLUSIONS Cough and fever were the most common symptom. Patients with comorbidities were in more serious condition. The detection of inflammatory indexes, coagulation function, lymphocyte subsets, and renal function can help diagnose and assess the severity of COVID-19.


Asunto(s)
/diagnóstico , Tos/epidemiología , Fiebre/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Coagulación Sanguínea/inmunología , /complicaciones , China/epidemiología , Comorbilidad , Tos/sangre , Tos/inmunología , Tos/virología , Femenino , Fiebre/sangre , Fiebre/inmunología , Fiebre/virología , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/inmunología , Inflamación/virología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Subgrupos de Linfocitos T/inmunología , Adulto Joven
4.
Front Endocrinol (Lausanne) ; 12: 626842, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790857

RESUMEN

Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells. Their local and systemic production and accumulation is associated with the etiology and progression of several inflammatory diseases, but the molecular mechanisms that underlie the biological activities of these oxidized phospholipids remain elusive. Increasing evidence highlights the ability of these stress mediators to modulate cellular metabolism and pro-inflammatory signaling in phagocytes, such as macrophages and dendritic cells, and to alter the activation and polarization of these cells. Because these immune cells serve a key role in maintaining tissue homeostasis and organ function, understanding how endogenous oxidized lipids reshape phagocyte biology and function is vital for designing clinical tools and interventions for preventing, slowing down, or resolving chronic inflammatory disorders that are driven by phagocyte dysfunction. Here, we discuss the metabolic and signaling processes elicited by endogenous oxidized lipids and outline new hypotheses and models to elucidate the impact of these lipids on phagocytes and inflammation.


Asunto(s)
Inflamación/fisiopatología , Fagocitos/inmunología , Fosfolípidos/metabolismo , Animales , /fisiopatología , Humanos , Inflamación/inmunología , Oxidación-Reducción
5.
Cells ; 10(3)2021 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-33799966

RESUMEN

The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) is responsible for COVID-19 infection. The COVID-19 pandemic represents one of the worst global threats in the 21st century since World War II. This pandemic has led to a worldwide economic recession and crisis due to lockdown. Biomedical researchers, pharmaceutical companies, and premier institutes throughout the world are claiming that new clinical trials are in progress. During the severe phase of this disease, mechanical ventilators are used to assist in the management of outcomes; however, their use can lead to the development of pneumonia. In this context, mesenchymal stem cell (MSC)-derived exosomes can serve as an immunomodulation treatment for COVID-19 patients. Exosomes possess anti-inflammatory, pro-angiogenic, and immunomodulatory properties that can be explored in an effort to improve the outcomes of SARS-CoV-2-infected patients. Currently, only one ongoing clinical trial (NCT04276987) is specifically exploring the use of MSC-derived exosomes as a therapy to treat SARS-CoV-2-associated pneumonia. The purpose of this review is to provide insights of using exosomes derived from mesenchymal stem cells in management of the co-morbidities associated with SARS-CoV-2-infected persons in direction of improving their health outcome. There is limited knowledge of using exosomes in SARS-CoV-2; the clinicians and researchers should exploit exosomes as therapeutic regime.


Asunto(s)
/terapia , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Inmunomodulación , Células Madre Mesenquimatosas/metabolismo , Neumonía Viral/terapia , /complicaciones , /patología , Citocinas/metabolismo , Citocinas/farmacología , Exosomas/química , Exosomas/genética , Humanos , Inflamación/inmunología , Inflamación/terapia , Inflamación/virología , Células Madre Mesenquimatosas/inmunología , Neovascularización Fisiológica/inmunología , Neumonía Viral/complicaciones , Neumonía Viral/virología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/terapia , Infecciones del Sistema Respiratorio/virología
6.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800244

RESUMEN

Hypoxia-induced mitogenic factor (HIMF), which is also known as resistin-like molecule α (RELM-α), found in inflammatory zone 1 (FIZZ1), or resistin-like alpha (retlna), is a cysteine-rich secretory protein and cytokine. HIMF has been investigated in the lung as a mediator of pulmonary fibrosis, inflammation and as a marker for alternatively activated macrophages. Although these macrophages have been found to have a role in acute liver injury and acetaminophen toxicity, few studies have investigated the role of HIMF in acute or immune-mediated liver injury. The aim of this focused review is to analyze the literature and examine the effects of HIMF and its human homolog in organ-specific inflammation in the lung and liver. We followed the guidelines set by PRISMA in constructing this review. The relevant checklist items from PRISMA were included. Items related to meta-analysis were excluded because there were no randomized controlled clinical trials. We found that HIMF was increased in most models of acute liver injury and reduced damage from acetaminophen-induced liver injury. We also found strong evidence for HIMF as a marker for alternatively activated macrophages. Our overall risk of bias assessment of all studies included revealed that 80% of manuscripts demonstrated some concerns in the randomization process. We also demonstrated some concerns (54.1%) and high risk (45.9%) of bias in the selection of the reported results. The need for randomization and reduction of bias in the reported results was similarly detected in the studies that focused on HIMF and the liver. In conclusion, we propose that HIMF could be utilized as a marker for M2 macrophages in immune-mediated liver injury. However, we also detected the need for randomized clinical trials and additional experimental and human prospective studies in order to fully comprehend the role of HIMF in acute or immune-mediated liver injury.


Asunto(s)
Lesión Renal Aguda/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Hígado/inmunología , Pulmón/inmunología , Macrófagos/inmunología , Acetaminofén/efectos adversos , Lesión Renal Aguda/patología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Pulmón/patología , Macrófagos/patología , Especificidad de Órganos/inmunología
7.
Cells ; 10(3)2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806810

RESUMEN

As highlighted by the COVID-19 global pandemic, elderly individuals comprise the majority of cases of severe viral infection outcomes and death. A combined inability to control viral replication and exacerbated inflammatory immune activation in elderly patients causes irreparable immune-mediated tissue pathology in response to infection. Key to these responses are type I, II, and III interferons (IFNs), which are involved in inducing an antiviral response, as well as controlling and suppressing inflammation and immunopathology. IFNs support monocyte/macrophage-stimulated immune responses that clear infection and promote their immunosuppressive functions that prevent excess inflammation and immune-mediated pathology. The timing and magnitude of IFN responses to infection are critical towards their immunoregulatory functions and ability to prevent immunopathology. Aging is associated with multiple defects in the ability of macrophages and dendritic cells to produce IFNs in response to viral infection, leading to a dysregulation of inflammatory immune responses. Understanding the implications of aging on IFN-regulated inflammation will give critical insights on how to treat and prevent severe infection in vulnerable individuals. In this review, we describe the causes of impaired IFN production in aging, and the evidence to suggest that these impairments impact the regulation of the innate and adaptive immune response to infection, thereby causing disease pathology.


Asunto(s)
Inmunidad Adaptativa , Envejecimiento/inmunología , Inmunidad Innata , Interferones/fisiología , Replicación Viral/inmunología , Anciano , /virología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/uso terapéutico , Interferón gamma/inmunología , Interferón gamma/uso terapéutico , Interferones/inmunología , Interferones/uso terapéutico
8.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807704

RESUMEN

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.


Asunto(s)
Alopecia Areata/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Dermatitis Atópica/inmunología , Adulto , Alopecia Areata/tratamiento farmacológico , Alopecia Areata/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Citocinas/inmunología , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Masculino , Persona de Mediana Edad , Receptores CCR4/inmunología , Receptores CXCR3/inmunología , Adulto Joven
9.
Cells ; 10(3)2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33808998

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.


Asunto(s)
/inmunología , Senescencia Celular/inmunología , Linfocitos T/inmunología , Timo/inmunología , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , Envejecimiento/patología , Autoinmunidad , /fisiopatología , Humanos , Inflamación/inmunología , Inflamación/patología , Timo/efectos de los fármacos , Timo/fisiopatología , Timo/virología
10.
RMD Open ; 7(1)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33790049

RESUMEN

BACKGROUND: The CHIC study (COVID-19 High-intensity Immunosuppression in Cytokine storm syndrome) is a quasi-experimental treatment study exploring immunosuppressive treatment versus supportive treatment only in patients with COVID-19 with life-threatening hyperinflammation. Causal inference provides a means of investigating causality in non-randomised experiments. Here we report 14-day improvement as well as 30-day and 90-day mortality. PATIENTS AND METHODS: The first 86 patients (period 1) received optimal supportive care only; the second 86 patients (period 2) received methylprednisolone and (if necessary) tocilizumab, in addition to optimal supportive care. The main outcomes were 14-day clinical improvement and 30-day and 90-day survival. An 80% decline in C reactive protein (CRP) was recorded on or before day 13 (CRP >100 mg/L was an inclusion criterion). Non-linear mediation analysis was performed to decompose CRP-mediated effects of immunosuppression (defined as natural indirect effects) and non-CRP-mediated effects attributable to natural prognostic differences between periods (defined as natural direct effects). RESULTS: The natural direct (non-CRP-mediated) effects for period 2 versus period 1 showed an OR of 1.38 (38% better) for 14-day improvement and an OR of 1.16 (16% better) for 30-day and 90-day survival. The natural indirect (CRP-mediated) effects for period 2 showed an OR of 2.27 (127% better) for 14-day improvement, an OR of 1.60 (60% better) for 30-day survival and an OR of 1.49 (49% better) for 90-day survival. The number needed to treat was 5 for 14-day improvement, 9 for survival on day 30, and 10 for survival on day 90. CONCLUSION: Causal inference with non-linear mediation analysis further substantiates the claim that a brief but intensive treatment with immunosuppressants in patients with COVID-19 and systemic hyperinflammation adds to rapid recovery and saves lives. Causal inference is an alternative to conventional trial analysis, when randomised controlled trials are considered unethical, unfeasible or impracticable.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteína C-Reactiva/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Metilprednisolona/uso terapéutico , /inmunología , Causalidad , Síndrome de Liberación de Citoquinas/inmunología , Estudio Históricamente Controlado , Humanos , Inflamación/inmunología , Mortalidad , Tasa de Supervivencia , Resultado del Tratamiento
11.
Mol Biol Rep ; 48(3): 2917-2928, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33837899

RESUMEN

The renin-angiotensin-aldosterone system and its metabolites play an important role in homeostasis of body, especially the cardiovascular system. In this study, we discuss the imbalance of multiple systems during the infection and the importance of therapeutic choice, dosing, and laboratory monitoring of cardiac and anti-coagulant therapies in COVID-19 patients. The crosstalk between angiotensin, kinin-kallikrein system, as well as inflammatory and coagulation systems plays an essential role in COVID-19. Cardiac complications and coagulopathies imply the crosstalks between the mentioned systems. We believe that the blockage of bradykinin can be a good option in the management of COVID-19 and CVD in patients and that supportive treatment of respiratory and cardiologic complications is needed in COVID-19 patients. Ninety-one percent of COVID-19 patients who were admitted to hospital with a prolonged aPTT were positive for lupus anticoagulant, which increases the risk of thrombosis and prolonged aPTT. Therefore, the question that is posed at this juncture is whether it is safe to use the prophylactic dose of heparin particularly in those with elevated D-dimer levels. It should be noted that timing is of high importance in anti-coagulant therapy; therefore, we should consider the level of D-dimer, fibrinogen, drug-drug interactions, and risk factors during thromboprophylaxis administration. Fibrinogen is an independent predictor of resistance to heparin and should be considered before thromboprophylaxis. Alteplase and Futhan might be a good choice to assess the condition of heparin resistance. Finally, the treatment option, dosing, and laboratory monitoring of anticoagulant therapy are critical decisions in COVID-19 patients.


Asunto(s)
Trombosis , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Bradiquinina/sangre , /inmunología , /terapia , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Inflamación/inmunología , Inflamación/virología , Calicreínas/sangre , Sistema Renina-Angiotensina/inmunología , Sistema Renina-Angiotensina/fisiología , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Trombosis/virología
12.
Front Immunol ; 12: 653344, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33868293

RESUMEN

Sepsis is a heterogeneous syndrome caused by a dysregulated host response during the process of infection. Neutrophils are involved in the development of sepsis due to their essential role in host defense. COVID-19 is a viral sepsis. Disfunction of neutrophils in sepsis has been described in previous studies, however, little is known about the role of microRNA-let-7b (miR-let-7b), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) activity in neutrophils and how they participate in the development of sepsis. In this study, we investigated the regulatory pathway of miR-let-7b/TLR4/NF-κB in neutrophils. We also explored the downstream cytokines released by neutrophils following miR-let-7b treatment and its therapeutic effects in cecal ligation and puncture (CLP)-induced septic mice. Six-to-eight-week-old male C57BL/6 mice underwent CLP following treatment with miR-let-7b agomir. Survival (n=10), changes in liver and lungs histopathology (n=4), circulating neutrophil counts (n=4), the liver-body weight ratio (n=4-7), and the lung wet-to-dry ratio (n=5-6) were recorded. We found that overexpression of miR-let-7b could significantly down-regulate the expression of human-derived neutrophilic TLR4 at a post-transcriptional level, a decreased level of proinflammatory factors including interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), and an upregulation of anti-inflammatory factor IL-10 in vitro. After miR-let-7b agomir treatment in vivo, neutrophil recruitment was inhibited and thus the injuries of liver and lungs in CLP-induced septic mice were alleviated (p=0.01 and p=0.04, respectively), less weight loss was reduced, and survival in septic mice was also significantly improved (p=0.013). Our study suggested that miR-let-7b could be a potential target of sepsis.


Asunto(s)
/inmunología , MicroARNs/inmunología , FN-kappa B/inmunología , Neutrófilos/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 4/inmunología , /patología , Humanos , Inflamación/inmunología , Inflamación/patología , Neutrófilos/patología
13.
Nat Commun ; 12(1): 2343, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879788

RESUMEN

In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.


Asunto(s)
Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Ácidos Siálicos/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Animales , Artritis Experimental/patología , Artritis Reumatoide/inmunología , Línea Celular , Citocinas/metabolismo , Regulación hacia Abajo , Fibroblastos/inmunología , Fibroblastos/metabolismo , Fibroblastos/patología , Glicosilación , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Masculino , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos DBA , Fenotipo , RNA-Seq , Sialiltransferasas/genética , Sialiltransferasas/metabolismo , Membrana Sinovial/inmunología , Transcriptoma
14.
Int J Mol Med ; 47(6)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33907833

RESUMEN

The biological abilities of interleukin­6 (IL­6) have been under investigation for nearly 40 years. IL­6 works through an interaction with the complex peptide IL­6 receptor (IL­6R). IL­6 is built with four α­chain nanostructures, while two different chains, IL­6Rα (gp80) and gp130/IL6ß (gp130), are included in IL­6R. The three­dimensional shapes of the six chains composing the IL­6/IL­6R complex are the basis for the nanomolecular roles of IL­6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL­6 have been identified. In the present review, the roles played by miRNA in the post­transcriptional regulation of IL­6 expression are evaluated. mRNAs are absorbed via the 'sponge' effect to dynamically balance mRNA levels and this has been assessed with regard to IL­6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL­6 signalling, two different IL­6 models have been proposed. IL­6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL­6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2; also known as COVID­19). In the present review, both inflammatory and cognitive IL­6 models were analysed by evaluating the cytological and histological locations of IL­6 signalling. The goal of this review was to illustrate the roles of the classic and trans­signalling IL­6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS­CoV­2 virus infection have been examined to determine the contribution of IL­6 to these disease states.


Asunto(s)
/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Animales , /inmunología , Cognición , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/inmunología , Interleucina-6/análisis , Interleucina-6/genética , Interleucina-6/inmunología , /fisiología
15.
Front Immunol ; 12: 598601, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33815361

RESUMEN

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.


Asunto(s)
/metabolismo , Ferroptosis , Hierro/metabolismo , Peroxidación de Lípido , Meningitis Criptocócica/metabolismo , Tuberculosis/metabolismo , /inmunología , Ferroptosis/inmunología , Glutatión/metabolismo , Humanos , Inflamación/inmunología , Metabolismo de los Lípidos , Meningitis Criptocócica/inmunología , Meningitis Criptocócica/patología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Tuberculosis/inmunología , Tuberculosis/patología
16.
J Immunother Cancer ; 9(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33837054

RESUMEN

The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/antagonistas & inhibidores , /aislamiento & purificación , /epidemiología , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Pandemias , /fisiología
17.
Nat Commun ; 12(1): 2130, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33837217

RESUMEN

Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for mito-SEPs that modify inflammatory outcomes and report a mito-SEP named "Modulator of cytochrome C oxidase during Inflammation" (MOCCI) that is upregulated during inflammation and infection to promote host-protective resolution. MOCCI, a paralog of the NDUFA4 subunit of cytochrome C oxidase (Complex IV), replaces NDUFA4 in Complex IV during inflammation to lower mitochondrial membrane potential and reduce ROS production, leading to cyto-protection and dampened immune response. The MOCCI transcript also generates miR-147b, which targets the NDUFA4 mRNA with similar immune dampening effects as MOCCI, but simultaneously enhances RIG-I/MDA-5-mediated viral immunity. Our work uncovers a dual-component pleiotropic regulation of host inflammation and immunity by MOCCI (C15ORF48) for safeguarding the host during infection and inflammation.


Asunto(s)
Complejo IV de Transporte de Electrones/genética , Pleiotropía Genética/inmunología , Inflamación/inmunología , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Línea Celular , Complejo IV de Transporte de Electrones/metabolismo , Técnicas de Inactivación de Genes , Humanos , Inflamación/genética , Inflamación/patología , Potencial de la Membrana Mitocondrial/inmunología , MicroARNs/genética , Mitocondrias/inmunología , Mitocondrias/patología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/inmunología
18.
Genome Med ; 13(1): 64, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879239

RESUMEN

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Asunto(s)
/inmunología , Citocinas/inmunología , Macrófagos/inmunología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colon/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Humanos , Inflamación/genética , Inflamación/inmunología , Pulmón/inmunología , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Fenotipo , RNA-Seq
19.
mBio ; 12(2)2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879594

RESUMEN

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.


Asunto(s)
Anticuerpos Antivirales , Inmunidad Innata , /inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Especificidad de Anticuerpos , Citotoxicidad Celular Dependiente de Anticuerpos , Biomarcadores/sangre , /virología , Estudios de Casos y Controles , Estudios de Cohortes , Activación de Complemento , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Inflamación/sangre , Inflamación/etiología , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Fagocitosis , Receptores Fc/inmunología , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/inmunología
20.
FASEB J ; 35(4): e21441, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33749902

RESUMEN

An excessive, non-resolving inflammatory response underlies severe COVID-19 that may have fatal outcomes. Therefore, the investigation of endogenous pathways leading to resolution of inflammation is of interest to uncover strategies for mitigating inflammation in people with SARS-CoV-2 infection. This becomes particularly urgent in individuals with preexisting pathologies characterized by chronic respiratory inflammation and prone to bacterial infection, such as cystic fibrosis (CF). Here, we analyzed the immune responses to SARS-CoV-2 virion spike 1 glycoprotein (S1) of macrophages (MΦ) from volunteers with and without CF and tested the efficacy of resolvins (Rv) D1 and D2 in regulating the inflammatory and antimicrobial functions of MΦ exposed to S1. S1 significantly increased chemokine release, including interleukin (IL)-8, in CF and non-CF MΦ, while it enhanced IL-6 and tumor necrosis factor (TNF)-α in non-CF MΦ, but not in CF cells. S1 also triggered the biosynthesis of RvD1 and modulated microRNAs miR-16, miR-29a, and miR-103, known to control the inflammatory responses. RvD1 and RvD2 treatment abated S1-induced inflammatory responses in CF and non-CF MΦ, significantly reducing the release of select chemokines and cytokines including IL-8 and TNF-α. RvD1 and RvD2 both restored the expression of miR-16 and miR-29a, while selectively increasing miR-223 and miR-125a, which are involved in NF-κB activation and MΦ inflammatory polarization. During Pseudomonas aeruginosa infection, S1 stimulated the MΦ phagocytic activity that was further enhanced by RvD1 and RvD2. These results provide a map of molecular responses to SARS-CoV-2 in MΦ, key determinants of COVID-19-related inflammation, unveiling some peculiarity in the response of cells from individuals with CF. They also demonstrate beneficial, regulatory actions of RvD1 and RvD2 on SARS-CoV-2-induced inflammation.


Asunto(s)
Fibrosis Quística , Ácidos Docosahexaenoicos/farmacología , Macrófagos , Infecciones por Pseudomonas , Pseudomonas aeruginosa/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , /inmunología , /patología , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Fibrosis Quística/virología , Citocinas/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Inflamación/virología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Macrófagos/virología , Masculino , MicroARNs/inmunología , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/patología , Infecciones por Pseudomonas/virología
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